Disease of diabetes mellitus is primarily due to an insufficiency of insulin action. Clinical diagnosis of diabetes is defined generally by typical symptoms of diabetes mellitus showing thirsty, polyuria and weight loss, with hyperglycemia and overflow glycosuria, indicating a plasma glucose level of over 200 mg/dl, or if the above symptoms are found by a blood sugar determination with generally a glucose tolerance test. Diabetes mellitus is often accompanied with various complication and a prognosis of diabetes mellitus is influenced by the complications. Angiopathy, a major complication of diabetes mellitus, is mainly classified in the micro angiopathy including diabetic retinopathy and diabetic nephropathy, and the macroangiopathy including ischemic heart disease and cerebrovascular disorder.
Diabetic nephropathy is an important chronic complication for the prognosis of diabetes mellitus. Accordingly, an early detection of diabetic nephropathyand an early prevention of its progress would be extremely desirable. Symptoms of diabetic nephropathy are defined, as illustrated in the reference [Diabetic Nephropathy, Ed. Friedman, E. A., p.75 (1986), FIGS. 5-8], by observing the level of urinary protein in the patients, as a term of temporary increase in exercise-induced microalbumin excretion followed by detecting persistent proteinuria with a yearly increase in protein and a gradual decrease in creatinine clearance as a result of progressing nephropathy.
Heretofore diabetic nephropathy in patients having diabetes mellitus has been diagnosed by appearance of clinically detectable proteinurea. In this clinical stage, histopathological changes markedly progressed with decreased renal function and the lesions appeared to be irreversible [Diabetes, Vol. 32, Suppl. 2, p.64 (183) and Diabetic Nephropathy, Ed, Friedman, E. A., p.65 (1986)].
Recently, trace urinaryalbumin could be detected by radioimmunoassay, and nephropathycan be diagnosed at an early stage prior to detecting persistent proteinurea [Diabetes, Vol. 32, Suppl. 2, p. 64 (1983)]. In the event that urinary trace albumin is detected, then further continued progress of 6-14 years persistent proteinuria can be observed. Urinary trace albumin is generally expressed by AER from timed excretion of urine, and has a threshold value of 15-30 .mu.g/min. The overflow value is defined as microalbuminuria and is diagnosed as diabetic nephropathy [Acta Endocrinol., 100:550 (1982), New Eng. J. Med., 331:89 (1983) and Lancet, 26:1430 (1982)].
Conventionally used parameters for reflecting renal function are urinary .beta.2-microglubulin and urinary NAG [J. Clin. Invest., 48:1189 (1969) and Toxicology, 23:99 (1982)]. However, these parameters are not sensitive markers for early diagnosis of diabetic nephropathy.
In patients of early diabetic nephropathy with detected microalbuminuria, there is a known mechanism for affecting a glomerular filtration barrier. Transglomerular passage of plasma proteins depends on the following factors, including 1) structural changes of glomerular membrane, 2) changes in renal hemodynamics such as renal plasma flow and transcapillary hydraulic pressure and 3) filtration surface area abnormalities in pore-size or pore-charge level [Diabetes Care, 9(5):529 (1986)]. At present, however, there is no known method for finding out renal function of disease in the stage of diabetic renal lesion without clinical sign of nephropathy before detecting urinary trace albumin. Accordingly it is earnestly desired to detect patients with high risk of developing diabetic nephropathy for early diagnosis.
Natural human parathyroid hormone (PTH) is a polypeptide consisting of 84 amino acids secreted by parathyroid gland and its major physiological actions are stimulating bone resorption and bone formation in the bone, and suppressing reabsorption of phosphorus and stimulating reabsorption of calcium in renal tubules. Biological activities of PTH are involved at the N-terminal in its structure and chains 1-34 have almost the same biological activity as the whole molecule of PTH. Receptor of PTH exists mostly in renal proximal tubules.
Mizunashi et al. reported that intravenous administration of human PTH(1-34) [generic name: Teriparatide acetate, Trade name: human PTH inj. (ASAHI KASEI), Manufacturer: ASAHI CHEMICAL INDUSTRY CO. LTD.] in patients of idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism (PHP) resulted in an increased urinary excretion of NAG in only IHP [Calcif. Tissue Int., 45(6):375 (1989)]. In addition, we have found that administration of human-PTH (1-34) in healthy volunteers resulted in an increased urinary excretion of NAG. Urinary NAG is a lysosomal enzyme widely located in renal proximal tubules, and is leaked from renal proximal tubular lysosome in the proximal tubular lesion, and is generally defined as a marker for toxicity of pharmaceuticals for the proximal tubular cells [Histochemistry, 63:245 (1979)].